Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

In a pancreatic tumor microenvironment,
activated pancreatic stellate
cells (PSCs) produce extracellular matrix (ECM) to form a barrier
to drug penetration. Moreover, the interaction between cancer cells
and activated PSCs promotes the tumor growth. Vitamin D receptor (VDR),
as a key regulator to promote the recovery of PSCs to the resting
state, is an attractive therapeutic target for pancreatic cancer.
Herein, we reported the design and synthesis of 57 nonsecosteroidal
VDR modulators based on the skeleton of phenyl-pyrrolyl pentane. Among
them, compounds C4, I5, and I8 exhibited excellent VDR affinity and effective inhibition of the
activation of PSCs, as well as potent suppression of the interaction
between cancer cells and PSCs in vitro. In
vivo, compound I5 combined with gemcitabine
achieved efficacious antitumor activity without causing hypercalcemia.
In conclusion, the compounds designed in our study can remodel the
tumor microenvironment and are expected to be candidates for the treatment
of pancreatic cancer.